Physiologically active substances such as various hormones, neurotransmitters and the like regulate the biological functions through specific receptor proteins present on cell membranes. Many of these receptor proteins are coupled with guanine nucleotide-binding protein (hereinafter sometimes simply referred to as G protein) and mediate the intracellular signal transduction through activation of G protein. These receptor proteins have the common structure having seven transmembrane domains and are thus collectively referred to as G protein-coupled receptor proteins or seven-transmembrane receptor proteins (7TMR).
G protein-coupled receptor proteins are present on the cell surface of each functional cell and organ in an organism, and play critical physiological roles as the target of the molecules that regulate the functions of the cell and organ, e.g., physiologically active substances such as peptide hormones, nucleic acids, amines, phospholipids, etc. Receptors transmit signals to cells through binding with physiologically active substances, and the signals induce various reactions such as activation or suppression of the cells.
To clarify the relationship between substances that regulate complex functions within cells and organs in various organisms, and their specific receptor proteins, in particular, G protein-coupled receptor proteins, would elucidate the functions of cells and organs in various organisms to provide a very important means for development of medicaments closely associated with these functions.
For example, in various organs, their physiological functions are controlled in vivo through regulation by many hormones, hormone-like substances, neurotransmitters or physiologically active substances. In particular, physiologically active substances are found in numerous sites of the body and regulate the physiological functions through their corresponding receptor proteins. Many unknown hormones, neurotransmitters or many other physiologically active substances are assumed to exist more in the body and, as to their receptor proteins, many of these proteins have not yet been reported. In addition, it is yet unknown if there are subtypes of known receptor proteins or differences between animal species.
It is a very important means for development of medicaments to clarify the relationship between substances that regulate elaborate functions in vivo and their specific receptor proteins. Further in development of drugs, it is required for efficient screening of agonists and antagonists of receptor proteins to clarify functional mechanisms of genes for the receptor protein expressed in vivo and express the genes in an appropriate expression system.
In recent years, random analysis of cDNA sequences has been actively studied as a means for analyzing genes expressed in vivo. The sequences of cDNA fragments thus obtained have been registered on and published to databases as Expressed Sequence Tag (EST). In addition, it has been extensively attempted to predict unknown genes based on the analysis of genomic sequences. However, since many ESTs or genomic sequences contain sequence information only, it is difficult to estimate their functions from that information.
The amino acid sequences of human-derived GPR39 and DNAs encoding the same are reported (Genomics 1997 Dec. 15, 46 (3): 426-34; WO 2002/61087; US 2002/004491; WO 2002/39885; WO 2002/71928; WO 2001/81634; WO 2002/79492; WO 2002/86443). However, the functions of these G protein-coupled receptor proteins and their physiological ligands remain unsolved.